Hypothesis paperHypothesis: the mitochondrial NO• signaling pathway, and the transduction of nitrosative to oxidative cell signals: an alternative function for cytochrome C oxidase
Introduction
In the mitochondrial field, several important insights have recently changed perspectives of this organelle in mammalian cells, including: (1) The release of the electron transfer protein, cytochrome c, to the cytosol can initiate programmed cell death or apoptosis [1]. (2) Mitochondria bind nitric oxide (NO•) specifically through an oxygen-sensitive process at cytochrome c oxidase [2], [3]. (3) Loss of control over mitochondrial superoxide (O2•−) and hydrogen peroxide (H2O2) levels in MnSOD knock out mice is fatal [4], [5]. (4) Specific uncoupling proteins (UCPs) have the potential to regulate mitochondrial H2O2 generation [6]. This hypothesis paper integrates these findings and suggests a potential role for the NO•-dependent inhibition of cytochrome c oxidase in providing the mediator for cross talk between nitrosative and oxidative redox signaling within the cell.
Section snippets
Nitrosative and oxidative cell signaling
The biochemistry of NO• is dominated by rapid reaction with other free radicals and by reversible binding to metalloproteins or to specific amino acid residues [7]. These reactions have the potential to initiate conformational changes in proteins that can activate or inhibit enzymes, a specific example being the activation of soluble guanylate cyclase (sGC) by NO• binding to the heme [8]. Modification of cysteine (thiol) residues by either S-nitrosylation or S-thiolation can also change
Mitochondrial H2O2 generation
A widely recognized intracellular source of O2•− or H2O2 is the mitochondrion [7], [17], [18]. Early studies clearly showed that mitochondria are capable of generating O2•−, principally at respiratory complex III [17], with the developing consensus that O2•− generation is controlled by the level of reduction of the respiratory chain. In intact mitochondria the presence of MnSOD in the mitochondrial matrix results in the conversion of O2•− to H2O2 [19]. The traditional perspective is one of O2•−
Control of mitochondrial H2O2 generation by NO• binding to cytochrome C oxidase
As discussed above, one factor controlling the mitochondrial generation of O2•− is the level of reduction of the respiratory chain. Since ATP synthesis is also coupled to respiratory chain activity, this would imply that mitochondrial H2O2 generation is linked to ATP synthesis. Can modulation of respiratory chain reduction occur independently from oxidative phosphorylation? If so, this would bring a potential signaling function for mitochondrially-generated H2O2 into the realm of normal
Mitochondrial H+ leak and H2O2
Additional mechanisms for controlling mitochondrial H2O2 generation would be anticipated if a signaling function is envisaged. In this regard, such a mechanism has recently been discovered in the form of uncoupling proteins (UCPs) [6], [34], indicating the potential for cross talk with other important metabolic pathways in the cell. The UCP family proteins are proposed to uncouple oxidative phosphorylation by mediating a leak of protons across the mitochondrial inner membrane [35]. When the
Mitochondrial control over NO• formation
In proposing a role for the interaction of NO• with cytochrome c oxidase in redox cell signaling, the possibility arises that mitochondria themselves may also impact on NO• formation. Indeed, this could be the underlying biological function for a putative mitochondrial NOS (mtNOS) that has been reported by a number of groups [38], [39]. This isoform of NOS has only recently been discovered and many aspects of its biological function remain uncharacterized. However, mtNOS regulation is thought
Conclusion
It is postulated that the NO•-dependent inhibition of cytochrome c oxidase in the mitochondrion represents a major NO• signaling pathway in the cell. The most important features of this hypothesis are shown in Fig. 2. It is proposed that NO•-dependent modulation of H2O2 by the mitochondrial respiratory chain is capable of transmuting nitrosative cell signals to the activation of oxidative signal transduction pathways. The mitochondrial antioxidant enzymes, particularly MnSOD, control the
Acknowledgements
This work was supported by grants from the American Heart Association, and the National Institutes of Health (HL58031, ES10167, AA12613).
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